Certain nitro-3-pyrinamines and 3-oxy-analogues

ABSTRACT

There are described compounds of the formula ##STR1## where n is 0 or 1; 
     X is O or NR 2 , R 2  being hydrogen, loweralkyl or loweralkylcarbonyl; 
     R is hydrogen, loweralkyl, arylloweralkyl or loweralkylcarbonyl; and 
     R 1  is ##STR2## wherein R 3  is hydrogen, loweralkyl or loweralkylcarbonyl; 
     m is 1 or 2; 
     each 
     R 4  is independently hydrogen or loweralkyl; and 
     Y is hydrogen, halogen, loweralkyl, loweralkoxy or trifluoromethyl; 
     which compounds are useful as topical antiinflammatory agents for the treatment of various dermatoses.

This is a division of a prior application Ser. No. 695,156, filed May 3,1991, now U.S. Pat. No. 5,221,682, which is a division of a priorapplication Ser. No. 603,086, filed Oct. 25, 1990, now U.S. Pat. No.5,034,403, which is a division of a prior application Ser. No. 496,723,filed Mar. 21, 1990, now U.S. Pat. No. 4,983,615, which is acontinuation-in-part of a prior application Ser. No. 372,509, filed Jun.28, 1989, now U.S. Pat. No. 4,970,219.

The present invention relates to compounds of Formula I, ##STR3## wheren is 0 or 1;

X is O or NR₂, R₂ being hydrogen, loweralkyl or loweralkylcarbonyl;

R is hydrogen, loweralkyl, arylloweralkyl or loweralkylcarbonyl; and

R₁ is ##STR4## wherein R₃ is hydrogen, loweralkyl or loweralkylcarbonyl;

m is 1 or 2;

each

R₄ is independently hydrogen or loweralkyl; and

Y is hydrogen, halogen, loweralkyl, loweralkoxy or trifluoromethyl;

which compounds are useful as topical antiinflammatory agents for thetreatment of various dermatoses including, for example, exogenousdermatitides (e.g. sunburn, photoallergic dermatitis, urticaria, contactdermatitis, allergic dermatitis), endogenous dermatitides (e.g. atopicdermatitis, seborrheic dermatitis, nummular dermatitis), dermatitides ofunknown etiology (e.g. generalized exfoliative dermatitis), and othercutaneous disorders with an inflammatory component (e.g. psoriasis).

Also included within the scope of this invention are compounds ofFormula II where n, X and R₁ are as defined above, which are useful forthe same dermatological applications as mentioned above and also asdirect precursors of the compounds of Formula I. ##STR5##

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1 to 6 carbon atoms. Examples of said loweralkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight- and branched-chain pentyl and hexyl.

The term halogen shall mean fluorine, chlorine, bromine or iodine.

The term aryl shall mean a phenyl group optionally mono-substituted witha loweralkyl, loweralkoxy, halogen or trifluoromethyl group.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical, geometrical andtautomeric isomers where such isomers exist.

The compounds of this invention are prepared by utilizing one or more ofthe synthetic steps described below.

Throughout the description of the synthetic steps, the notations R, R₁,R₂, R₃, R₄, X, Y, m and n shall have the respective meanings given aboveunless otherwise stated or indicated, and other notations shall have therespective meanings defined in their first appearances unless otherwisestated or indicated.

STEP A

A compound of Formula III where Hal is F or Cl, preferably F, is allowedto react with a compound of Formula IV where M is Na, K or Li to afforda compound of Formula V. ##STR6##

This reaction is typically conducted in a suitable solvent such asethanol, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone ata temperature of about 0° to 150° C.

3-Fluoro-4-nitropyridine-N-oxide, which belongs to the group ofcompounds of Formula III, is disclosed in Talik and Talik, RocznikiChemii, Volume 38, 777 (1964). 4-Chloro-3-nitropyridine, which alsobelongs to the group of compounds of Formula III, is disclosed in Talik,et al., Roczniki Chemii, Volume 43(5), 923 (1969).

STEP B

Compound III is allowed to react with a compound of Formula VI to afforda compound of Formula VII. ##STR7##

This reaction is typically conducted in the presence of a suitablesolvent such as ethanol, dimethylformamide, dimethylsulfoxide orN-methylpyrrolidone at a temperature of about 0° to 150° C.

STEP C

Compound VII is allowed to react with a compound of the formula, R₂-Hal, where R₂ is loweralkyl, arylloweralkyl or loweralkylcarbonyl andHal is bromine or chlorine in a routine manner known to the art toafford a compound of Formula VIII. ##STR8##

STEP D

A compound of Formula IX which is obtained from STEP A, B or C isselectively hydrogenated to afford a compound of Formula X. ##STR9##

This selective hydrogenation is typically conducted with the aid of asuitable catalyst such as Pd/C, Pt/C or PtO₂ and a suitable medium suchas ethanol at a temperature of about 20° to 80° C.

STEP E

Compound IX is catalytically hydrogenated in a manner similar to the onedescribed in STEP D above, except that a longer reaction period orhigher reaction temperature is preferably employed, to afford a compoundof Formula XI. ##STR10##

Instead of using compound IX in the above reaction, one can also usecompound X and conduct the hydrogenation in substantially the samemanner as described above to obtain compound XI.

STEP F

A compound of Formula XII obtained from STEP D, E or G is allowed toreact with a compound of the formula, R₅ -Hal, where R₅ is loweralkyl,arylloweralkyl or loweralkylcarbonyl and Hal is bromine or chlorine, ina routine manner known to the art to afford a compound of Formula XIII.##STR11##

STEP G

Compound IX is reduced with a titanium (0) reagent in a routine mannerknown to the art to afford Compound XI. ##STR12##

Typically, the titanium (0) reagent is prepared by combining a reducingagent, such as lithium aluminum hydride or magnesium metal, to titaniumtetrachloride in an ethereal solvent such as tetradydrofuran, diethylether, diisopropyl ether, or 1,2-dimethoxyethane.

Compounds of Formula I and Formula II according to this invention areuseful as topical agents for the treatment of various skin disorderssuch as those mentioned earlier. The dermatological activities of thecompounds of this invention were ascertained with reference to thefollowing methods.

DERMATOLOGICAL TEST METHODS Phospholipase A₂ -induced Paw Edema (PIPE)

The ability of compounds to prevent naja naja (snake venom)phospholipase A₂ -induced paw edema in male Wistar rats (100-125 g) wasmeasured. PLA₂ (3 units/paw) alone or with 0.1M of the test compound wasinjected in the subplantar region of the rat left hindpaw. Immediatelysubsequent to the injection and at two hours post administration the pawwas immersed in a mercury bath, and paw displacement was measured on arecorder via a transducer. (Standard: hydrocortisone ED₅₀ =0.46M). SeeGiessler, A. J. et al., Agents and Actions, Vol. 10, Trends inIntimation Research (1981), p. 195.

In Vitro Phospholipase A₂ Assay (PLA₂)

The ability of a compound to modulate PLA₂ activity (cleavage of ¹⁴C-dipalmitoyl phosphotidylcholine at the 2-position to ¹⁴ C-palmiticacid) was quantitated in this assay. The reaction mixture contained Trisbuffer (25 mM), pH 8.0, calcium chloride (2.0 mM), bovine serum albumin(0.5 mg), dipalmitoyl phosphotidylcholine (8×10⁻⁵ M), (¹⁴C-palmitoyl)dipalmitoyl phosphotidylcholine (6×10³ cpm), porcinepancreatic PLA₂ (3.2 units) and the test compound. The reaction was runat 37° C. in a shaking incubator. The reaction was quenched and aninternal standard was added in order to determine sample recovery. Thesamples were loaded onto C₁₈ columns, eluted with ethanol, and theradioactivity was then measured. (Standard: quinacrine IC₅₀ =3.5×10⁻⁴M). See Feyen, J. H. M., et al., Journal of Chromatography 259 (1983),pp. 338-340.

Arachidonic Acid-Induced Ear Edema (AAEE)

The purpose of this assay was to determine the ability of atopically-applied compound to prevent mouse ear edema induced by topicalapplication of arachidonic acid. Female Swiss Webster mice topicallyreceived vehicle or test compound (1.0 mg/ear) on both ears (10 μl onouter and inner ears). After 30 minutes, the right ear of all groupsreceived arachidonic acid (4 mg/ear) and the left ear received vehiclealone. After an additional 1 hour, the mice were sacrificed and an earpunch (4 mm) was taken from each ear. The difference in right and leftear punch weights for each animal was determined to assess activity.(Standard: indomethacin ED₅₀ =1.5 mg/ear). See Young, J. M. et al.,Invest. Dermatol., 80, (1983), pp 48-52.

TPA-Induced Ear Edema (TPAEE)

The purpose of this assay was to determine the ability of atopically-applied compound to prevent ear edema induced by topicalapplication of TPA (phorbol 12-myristate acetate). Female Swiss Webstermice topically received TPA (10 μg/ear) on the right ear and vehicle onthe left ear. The test compound (10 μg/ear) was applied to both ears.After five hours, the animals were sacrificed ,and an ear punch (4 mm)was taken from each ear. The difference in right and left ear punchweights for each animal was determined to assess activity. (Standard:hydrocortisone ED₅₀ =47 μg/ear). See Young, J. M. et al., J. Invest.Dermatol., 80 (1983), pp. 48-52.

Cultured Human Keratinocyte DNA Synthesis (in vitro DNA)

The effect of a compound on the proliferation of cultured humanepidermal keratinocytes was measured. After incubation with a testcompound for 24 hours, the cultures were pulse-labelled for three hourswith 5 μCi of ³ H-thymidine. The cultures were extracted for DNAsuccessively with trichloroacetic acid and ethanol, and thereafterdissolved with NaOH. The radioactive incorporation of ³ H-thymidine intoDNA was determined. (Standard: indomethacin IC₅₀ =3.8×10⁻⁵ M).

Epidermal DNA Synthesis (in vivo DNA)

The influence of compounds on the proliferation of skin was assessed bydetermining inhibition or stimulation of DNA synthesis. HRS/J hairlessmice received topical application of a compound or vehicle alone on thedorsal aspect. After 24 hours, ³ H-thymidine (25 μCi) was administeredby intraperitoneal injection. After an additional hour, animals weresacrificed and the dorsal skin was removed. The epidermal layer waspeeled from the dermis by heat separation. Unincorporated ³ H-thymidinewas removed by washing successively with trichloroacetic acid andethanol. Samples were centrifuged at 2,000 rpm and supernatantsdiscarded. The epidermal sheets were then extracted with warmtrichloroacetic acid and the supernatants analyzed for ³ H-thymidineincorporation by scintillation counting and total DNA by a standardcolorimetric assay. (Standard: indomethacin ED₅₀ =1.75 mg/animal). SeeLowe, N. J., et al., Arch. Dermatol., 117 (1981), pp. 394-8; and Burton,K., Biochem. J. 62 (1956), pp. 315-22.

Dermatological activities for some of the compounds of this inventionare presented in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                                   in vivo                                                                            in vitro                                               PIPE*                                                                             PLA.sub.2 *                                                                        AAEE                                                                              TPAEE                                                                              DNA  DNA                                       Compound     (0.1M)                                                                            (0.01M)                                                                            (1 mg)                                                                            (10 μg)                                                                         (2.5 mg)                                                                           (50 μM)                                __________________________________________________________________________    N-(4-Nitro-3-pyridinyl)-                                                                       -71%                                                         1H-indol-5-amine,                                                             N.sup.5 -oxide                                                                1-Methyl-N-  -41%                                                                              -66%     -30%                                                (4-nitro-3-pyridinyl)-1H-                                                     indol-5-amine, N.sup.5 -oxide                                                 N-(3-Nitro-      -36%                                                         4-pyridinyl)-1H-indol-                                                        5-amine                                                                       N-(4-Nitro-               -40%                                                3-pyridinyl)-1H-indol-                                                        7-amine, N.sup.7 -oxide                                                       N-(4-Nitro-               -78%                                                3-pyridinyl)-1H-indazol-                                                      5-amine, N.sup.5 -oxide                                                       N-(4-Nitro-      -83%                                                         3-pyridinyl)-1H-indazol-                                                      6-amine, N.sup.6 -oxide                                                       N-(Indan-5-yl)-4-nitro                                                                              -44%                                                                              -48%                                                3-pyridinamine-1-oxide                                                        1N-(Indan-1-yl)-          -65%                                                4-nitro-3-                                                                    pyridinamine-1-oxide                                                          N-(4-Amino-  -67%                                                                              -87% -41%                                                                              -85% -27% -81%                                      3-pyridinyl)-                                                                 H-indol-5-amine                                                               N-(4-Amino-  -42%                                                                              -62%                                                         3-pyridinyl)-                                                                 1-methyl-1H-indol-5-amine                                                     N-(3-Amino-      -82% -37%                                                    4-pyridinyl)-                                                                 1H-indol-5-amine                                                              3-[(1H-      -62%                                                                              -34% -50%                                                                              -42% -37%                                           Indol-5-yl)-                                                                  oxy]-4-pyridinamine                                                           1-Acetyl-N-           -36%                                                    (4-amino-3-                                                                   pyridinyl)-2,3-dihydro-                                                       1H-indol-5-amine                                                              4-[(1H-      -52%                                                             Indol-5-yl)-                                                                  oxy]-3-pyridinamine                                                           N.sup.3 -(Indan-      -49%                                                                              -75%                                                5-yl)-3,4-pyridinediamine                                                     N-(4-Amino-  -45%         -38%                                                3-pyridinyl)-                                                                 1H-indol-7-amine,                                                             N.sup.7 -oxide                                                                N-(4-Amino-      -57% -35%                                                    3-pyridinyl)-                                                                 1H-indazol-6-amine                                                            __________________________________________________________________________     *difference in edema vs. control                                         

Examples of the compound of this invention include:

N-(4-Amino-3-pyridinyl)-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-1-methyl-1H-indol-5-amine;

N-(3-Amino-4-pyridinyl)-1H-indol-5-amine;

3-[(1H-Indol-5-yl)oxy]-4-pyridinamine;

1-Acetyl-N-(4-amino-3-pyridinyl)-2,3-dihydro-1H-indol-5-amine;

4-[(1H-Indol-5-yl)oxy]-3-pyridinamine;

N³ -(Indan-5-yl)-3,4-pyridinediamine;

N-(4-Amino-3-pyridinyl)-1H-indazol-5-amine;

N-(4-Amino-3-pyridinyl)-1H-indol-7-amine, N⁷ -oxide;

N-(4-Amino-3-pyridinyl)-1H-indol-7-amine;

N-(4-amino-3-pyridinyl)-1H-indazol-6-amine;

N-(4-Nitro-3-pyridinyl)-1H-indol-5-amine, N⁵ -oxide;

1-Methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N⁵ -oxide;

N-(3-Nitro-4-pyridinyl)-1H-indol-5-amine;

N-(4-Nitro-3-pyridinyl)-1H-indol-7-amine, N⁷ -oxide;

1-Acetyl-2,3-dihydro-N-(4-nitro-3-pyridinyl)-1H-indole-5-amine, N⁵-oxide;

N-(4-Nitro-3-pyridinyl)-1H-indazol-5-amine, N⁵ -oxide;

N-(4-Nitro-3-pyridinyl)-1H-indazol-6-amine, N⁶ -oxide;

N-(Indan-5-yl)-4-nitro-3-pyridinamine-1-oxide;

N-(Indan-1-yl)-4-nitro-3-pyridinamine-1-oxide;

5-[(4-Nitro-3-pyridinyl)oxy]-1H-indole, N⁵ -oxide;

5-[(3-Nitro-4-pyridinyl)oxy]-1H-indole;

N-(4-Amino-3-pyridinyl)-2-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-2-methyl-1H-indol-5-amine N⁵ -oxide;

N-(4-Amino-3-pyridinyl)-2,3-dimethyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-chloro-2,3-dimethyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-2,3-dimethyl-1H-indol-5-amine-N⁵ -oxide;

N-(4-Amino-3-pyridinyl)-N,2,3-trimethyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-2,3-dimethyl-7-iodo-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-chloro-2-ethyl-3-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-chloro-3-ethyl-2-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-2,3-dimethyl-7-trifluoromethyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-2,3-dimethyl-7-methoxy-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-3-isopropyl-2-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-chloro-2-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-chloro-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-7-methyl-1H-indol-5-amine;

N-(4-Amino-3-pyridinyl)-3-ethyl-1H-indol-5-amine; and

N-(4-Amino-3-pyridinyl)-7-bromo-2,3-dimethyl-1H-indol-5-amine.

The following examples are presented in order to illustrate thisinvention:

EXAMPLE 1 N-(4-Nitro-3-pyridinyl)-1H-indol-5-amine, N⁵ -oxide

A solution of 3-fluoro-4-nitropyridine-1-oxide¹ (5 g) and1H-indol-5-amine (4.2 g) in 100 ml ethanol was warmed to 80° for onehour and thereafter cooled, and the product was filtered to give 8 gsolid, d 244°. Three grams were recrystallized from acetonitrile to give2.6 g solid, d 244°-245°.

Analysis: Calculated for C₁₃ H₁₀ N₄ O₃ : 57.77% C, 3.73% H, 20.74% N;Found 57.99% C, 3.66% H, 20.91% N.

EXAMPLE 2 1-Methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N⁵ -oxide

A solution of 3-fluoro-4-nitropyridine-1-oxide (6 g) and1-methyl-1H-indol-5-amine (5.5 g) in 125 ml ethanol was warmed on asteam bath for thirty minutes and thereafter cooled, diluted with etherand filtered to give 10 g solid, d 232°-234°. Three grams wererecrystallized from ethanol to give 2.2 g needles, d 237°-238°.

Analysis: Calculated for C₁₄ H₁₂ N₄ O₃ : 59.15% C, 4.25% H, 19.71% N;Found: 59.31% C, 4.20% H, 19.71% N.

EXAMPLE 3 N-(3-Nitro-4-pyridinyl)-1H-indol-5-amine

To 150 ml of absolute ethanol were added 1H-indol-5-amine (8.06 g),4-chloro-3-nitropyridine (10.0 g) and triethylamine (8.5 ml), and thismixture was heated to 60° C. and stirred for 2 hours. The mixture wascooled, the ethanol evaporated, and the residue taken up in awater/ethyl acetate mixture. This was treated with Na₂ CO₃ (aq) toadjust the pH to 10. The organic layer was collected, the aqueous layerextracted again with ethyl acetate, and the organics were combined,washed with water and dried (sat. NaCl, anh. MgSO₄).

After filtration, the solvent was evaporated to yield a solid (14.2 g)which was eluted with 5% ethyl acetate/DCM on a silica gel column viaflash method. The desired fractions were concentrated to yield a solid(6.1 g). Of this material, 2.0 g was recrystallized from absoluteethanol to yield a solid, 1.2 g, m.p. 204°-206° C.

Analysis: Calculated for C₁₃ H₁₀ N₄ O₂ : 61.41% C, 3.96% H, 22.04% N;Found: 61.41% C, 3.96% H, 22.00% N.

EXAMPLE 4 N-(4-Nitro-3-pyridinyl)-1H-indol-7-amine, N⁷ -Oxide

To 200 ml ethanol were added 3-fluoro-4-nitropyridine-1-oxide (6.0 g)and 1H-indol-7-amine (5.5 g). After stirring at 85° C. for four hours,the mixture was cooled, and the precipitate was collected, washed withmethanol, and dried at 60° C. overnight to give 9.9 g of solid, m.p.250° C.

Analysis: Calculated for C₁₃ H₁₀ N₄ O₃ : 57.78% C, 3.73% H, 20.73% N;Found: 57.37% C, 3.54% H, 20.40% N.

EXAMPLE 51-Acetyl-2,3-dihydro-N-(4-nitro-3-pyridinyl)-1H-indole-5-amine, N⁵-Oxide

A solution of 3-fluoro-4-nitropyridine-1-oxide (4.5 g) and1-acetyl-2,3-dihydro-1H-indol-5-amine (5 g) in 100 ml ethanol wasstirred for two hours at reflux, and thereafter cooled and filtered togive 8.5 g crystals, d 239°-240°. Four grams were recrystallized fromacetonitrile/ether to give 3 g crystals, d 255°-256°.

Analysis: Calculated for C₁₅ H₁₄ N₄ O₄ : 57.32% C, 4.49% H, 17.83% N;Found: 57.26% C, 4.49% H, 17.69% N.

EXAMPLE 6 N-(4-Nitro-3-pyridinyl)-1H-indazol-5-amine, N⁵ -Oxide

A mixture of 3-fluoro-4-nitropyridine-1-oxide (6 g) and1H-indazol-5-amine (5.2 g) in 150 ml of ethanol was refluxed for twohours, and thereafter was cooled, diluted with ether and filtered togive 10 g solid. A 3.5 g portion was recrystallized from ethanol to give3.0 g solid, d 250°.

Analysis: Calculated for C₁₂ H₉ N₅ O₃ : 53.13% C, 3.34% H, 25.83% N;Found: 52.84% C, 3.34% H, 25.36% N.

EXAMPLE 7 N-(4-Nitro-3,pyridinyl)-1H-indazol-6-amine, N⁶ -Oxide

To 100 ml of ethanol were added 3-fluoro-4-nitropyridine-1-oxide (6.0 g)and 1H-indazol-6-amine (5.5 g) and this mixture was heated to 70° C. andstirred for four hours. The mixture was filtered to yield a solid (9.5g) which was recrystallized from methanol to yield a solid, 6.0 g, m.p.247°-248° C. (decomposed).

Analysis: Calculated for C₁₂ H₉ N₅ O₃ : 53.14% C, 3.34% H, 25.82% N;Found: 52.96% C, 3.17% H, 25.72% N.

EXAMPLE 8 N-(Indan-5-yl)-4-nitro-3-pyridinamine-1-oxide

A solution of 3-fluoro-4-nitropyridine-1-oxide (12 g) and indan-5-amine(10 g) in 200 ml ethanol was stirred at reflux for two hours, andthereafter cooled, diluted with ether and filtered to give 19 g solid,m.p. 195°. Four grams were recrystallized from ethanol to give 2.6 gcrystals, m.p. 194°-195°.

Analysis: Calculated for C₁₄ H₁₃ N₃ O₃ : 61.98% C, 4.83% H, 15.49% N;Found: 62.01% C, 4.89% H, 15.42% N.

EXAMPLE 9 N-(Indan-1-yl)-4-nitro-3-pyridinamine-1-oxide

A solution of 3-fluoro-4-nitropyridine-1-oxide (5.6 g) and indan-1-amine(6 g) in 100 ml ethanol was stirred at reflux for one hour andthereafter cooled and concentrated to 12 g of solid. This solid waspurified by flash chromatography (silica, ethyl acetate indichloromethane) to give 9.2 g solid, m.p. 137°-138°. An analyticalsample was obtained by recrystallizing 2.7 g from ethanol to give 2.5 gcrystals, m.p. 141°-142°.

Analysis: Calculated for C₁₄ H₁₃ N₃ O₃ : 61.98% C, 4.83% H, 15.49% N;Found: 62.11% C, 4.89% H, 15.59% N.

EXAMPLE 10 5-[(4-Nitro-3-pyridinyl)oxy]-1H-indole, N⁵ -Oxide

A solution of 5-hydroxyindole (4.8 g) in 20 ml dimethylformamide wasslowly added to an ice cooled suspension of sodium hydride (0.9 g) in 5ml dimethylformamide. After the anion formation, a solution of3-fluoro-4-nitropyridine-1-oxide (5.7 g) in 20 ml dimethylformamide wasadded. After one hour the reaction mixture was stirred with ice water,extracted with chloroform and filtered. The organic extract was washedwith water and saturated sodium chloride solution, dried (anhy. MgSO₄),filtered and concentrated to 3.5 g oil. This oil was purified by flashchromatography (silica, 20% ethyl acetate in dichloromethane) to give2.2 g solid, d 208-210°. This was combined with 2 g product obtainedfrom another condensation and recrystallized from ethanol to give 3 g, d216°-218°.

Analysis: Calculated for C₁₃ H₉ N₃ O₄ : 57.57% C, 3.34% H, 15.49% N;Found: 57.41% C, 3.36% H, 15.39% N.

EXAMPLE 11 5-[(3-nitro-4-pyridinyl)oxy]-1H-indole

To a solution of 5-hydroxyindole (7.45 g) in 100 ml of DMF was added K₂CO₃ (10.4 g). This mixture was stirred for 10 minutes at roomtemperature and then a solution of 4-chloro-3-nitropyridine (11.89 g) in50 ml DMF was added dropwise. The reaction was allowed to proceed for 24hours at room temperature. The mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with waterand saturated NaCl solution and dried over MgSO₄. After filtration, thesolvent was evaporated to yield an oil (15.4 g). This material waseluted with 5% ethyl acetate/DCM on a silica gel column via HPLC. Thedesired fractions were concentrated to yield a solid, 1.35 g, m.p.182°-184° C.

EXAMPLE 12 N-(4-Amino-3-pyridinyl)-1H-indol-5-amine

A mixture of N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N⁵ -oxide (7.8 g)in 500 ml ethanol containing platinum oxide (1.25 g) was hydrogenated at50 psi for six hours and thereafter filtered and concentrated. Theproduct was purified by flash chromatography (silica, 20% methanol indichloromethane) to give 6 g solid, m.p. 83°-90°. Three grams weredistilled twice via Kugelrohr (240°-250° @0.01 mm Hg) to give 2.4 gsolid, 138°-140°.

Analysis: Calculated for C₁₃ H₁₂ N₄ : 69.62% C, 5.39% H, 24.99% N;Found: 69.21% C, 5.47% H, 24.80% N.

EXAMPLE 13 N-(4-Amino-3-pyridinyl)-1-methyl-1H-indol-5-amine

A suspension of 1-methyl-N-(4-nitro-3-pyridinyl)-1H-indol-5-amine, N⁵-oxide (6.8 g) in 250 ml ethanol containing 0.4 g platinum oxide washydrogenated at 50 psi for twenty hours and thereafter filtered throughCelite and concentrated to 3.5 g oil. This oil was purified by HPLC(silica 20% methanol in ethyl acetate) to give 2.5 g solid, m.p.167°-169°. This solid was recrystallized from acetonitrile/ether to give1.1 g solid, m.p. 168°-169°.

Analysis: Calculated for C₁₄ H₁₄ N₄ : 70.57% C, 5.92% H, 23.51% N;Found: 70.44% C, 5.96% H, 23.39% N.

EXAMPLE 14 N-(3-Amino-4-pyridinyl)-1H-indol-5-amine

To a slurry of 10% Pd/C (1.0 g) in 10 ml of methanol was addedN-(3-nitro-4-pyridinyl)-1H-indol-5-amine (4.0 g) in 230 ml methanol andthis mixture was hydrogenated at 50 psi on a Parr apparatus. When thereaction was complete, the mixture was filtered through Celite and thefiltrate concentrated to yield a solid (3.9 g). This material was elutedwith 20% methanol/DCM on a silica gel column via HPLC. The desiredfractions were concentrated to yield a solid (2.45 g) which wasrecrystallized from ethanol/water (10:1) to yield a solid, 1.8 g, m.p.159°-161 ° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ : 69.62% C, 5.39% H, 24.98% N;Found: 69.63% C, 5.46% H, 25.07% N.

EXAMPLE 15 3-[(1H-Indol-5-yl)oxy]-4-pyridinamine

A suspension of 5-[(4-nitro-3-pyridinyl)oxy]-1H-indole, N⁵ -oxide (10 g)in 250 ml ethanol containing 0.4 g PtO₂ was hydrogenated at 50 psi for25 hours and thereafter filtered through Celite and concentrated to 9 goil. This oil was purified by HPLC (silica, 10% methanol in ethylacetate) to give 3.5 g solid. This solid was recrystallized fromacetonitrile to give 2.4 g crystals, m.p. 170°-172°.

Analysis: Calculated for C₁₃ H₁₁ N₃ O: 69.32% C, 4.92% H, 18.65% N;Found: 69.28% C, 4.80% H, 18.57% N.

EXAMPLE 16 1-Acetyl-N-(4-amino-3-pyridinyl)-2,3-dihydro-1H-indol-5-amine

A suspension of1-acetyl-2,3-dihydro-N-(4-nitro-3-pyridinyl)-1H-indole-5-amine, N⁵-oxide (13 g) in 250 ml ethanol containing 0.5 g PtO₂ was hydrogenatedfor two days at 60 psi and thereafter filtered through Celite andconcentrated to 9 g solid. This solid was purified by HPLC (silica, 20%methanol in ethyl acetate) to give 4 g solid. This was combined with 1 gproduct obtained from a previous reduction and again purified by HPLC(silica, 20% methanol in ethyl acetate) to give 5 g solid, m.p.210°-212°. This solid was recrystallized from acetonitrile to give 4 gsolid, m.p. 212°-214°.

Analysis: Calculated for C₁₅ H₁₆ N₄ O: 67.15% C, 6.01% H, 20.88% N;Found: 66.84% C, 5.95% H, 20.80% N.

EXAMPLE 17 4-[(1H-Indol-5-yl)oxy]-3-pyridinamine

To a slurry of 10% Pd/C (1.0 g) in 10 ml of ethanol was added5-[(3-nitro-4-pyridinyl)oxy]-1H-indole (3.7 g) in 240 ml ethanol andthis was shaken on a Parr apparatus for 1 hour. The mixture was filteredand the filtrate concentrated to yield an oil (3.1 g) which was elutedwith ethyl acetate on a silica gel column via HPLC. The desiredfractions were concentrated to an oil which solidified on standing toyield2.6 g, m.p. 155°-157° C.

Analysis: Calculated for C₁₃ H₁₁ N₃ O: 69.32% C, 4.92% H, 18.65% N;Found: 69.13% C, 4.94% H, 18.46% N.

EXAMPLE 18 N³ -(Indan-5-yl)-3,4-pyridinediamine

A solution of

N-(indan-5-yl)-4-nitro-3-pyridinamine-1-oxide (10 g) in 250 ml ethanolcontaining 0.4 g PtO₂ was hydrogenated at 60 psi for 24 hours andthereafter filtered through Celite and concentrated to 10 g oil. Thisoil was purified by flash chromatography (silica, 5% methanol in ethylacetate ) to give 8.3 g thick oil. This oil was crystallized in diethylether to give 5.5 g solid, m.p. 109°-110°.

Analysis: Calculated for C₁₄ H₁₅ N₃ : 74.64% C, 6.71% H, 18.65% N;Found: 74.81% C, 6.72% H, 18.71% N.

EXAMPLE 19 N-(4-Amino-3-pyridinyl)-1H-indazol-5-amine

A suspension of N-(4-nitro-3-pyridinyl)-1H-indazol-5-amine, N⁵ -oxide (7g) in 250 ml ethanol containing 0.5 g platinum oxide was hydrogenated at60 psi for sixty hours and thereafter filtered through Celite andconcentrated to 3.3 g solid. This solid was purified by HPLC (silica,25% methanol in dichloromethane) to give 2.1 g solid. This solid wasrecrystallized twice from acetonitrile to give 1.5 g crystals, m.p.198°-199°

Analysis: Calculated for: C₁₂ H₁₁ N₅ : 63.98% C, 4.92% H, 31.10% N;Found: 63.66% C, 4.88% H, 30.94% N.

EXAMPLE 20 N-(4-Amino-3-pyridinyl)-1H-indol-7-amine, N⁷ -Oxide

To 250 ml ethanol in a 500 ml Parr hydrogenation bottle were addedN-(4-nitro-3-pyridinyl)-1H-indol-7-amine, N⁷ -oxide (5.0 g) and 0.4 gPtO₂. After shaking at ambient temperature for twenty-two hours underfifty psi hydrogen, the mixture was filtered and concentrated to a foam,4.8 g.

This foam was eluted on a silica gel column with 30% methanol/DCM viaHPLC. The desired fractions were combined and concentrated to a solid,2.8 g, m.p. >250° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ O: 64.99% C, 5.03% H, 23.32% N;Found: 64.57% C, 5.12% H, 22.78% N.

EXAMPLE 21 N-(4-Amino-3-pyridinyl)-1H-indol-7-amine

To 250 ml ethanol in a 500 ml Parr hydrogenation bottle, were addedN-(4-amino-3-pyridinyl)-1H-indol-7-amine, N⁷ -oxide (2.8 g) and 0.3 gPtO₂. The mixture was shaken at ambient temperature under fifty psihydrogen for one hour, and thereafter filtered and concentrated to anoil, (2.7 g). This oil was eluted on a silica gel column with 30%methanol/DCM via HPLC. The desired fractions were combined andconcentrated to a solid, 2.1 g, m.p. 68°-70° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ : 69.62% C, 5.40% H, 24.98% N;Found: 68.98% C, 5.48% H, 24.79% N.

EXAMPLE 22 N-(4-Amino-3-pyridinyl)-1H-indazol-6-amine

To PtO₂ (0.3 g) in 10 ml of ethanol was addedN-(4-nitro-3-pyridinyl)-1H-indazol-6-amine, N⁶ -oxide (2.0 g) in 240 mlof ethanol and this was hydrogenated on a Parr apparatus at 60 psi for20 hours. The mixture was filtered and concentrated to an oil (2.1 g).This material was eluted with 20% methanol/DCM on a silica gel columnvia HPLC. The desired fractions were concentrated to a solid (0.7 g),which was recrystallized from acetonitrile to yield a solid 0.5 g, m.p.214°-216° C.

Analysis: Calculated for C₁₂ H₁₁ N₅ : 63.99% C, 4.92% H, 31.09% N;Found: 64.16% C, 4.92% H, 31.23% N.

EXAMPLE 23 N-(4-Amino-3-pyridinyl)-2-methyl-1H-indol-5-amine Ethanolate

A mixture of 4-nitro-3-fluoropyridine N-oxide (5.4 g) and5-amino-2-methylindole (5.0 g) in 100 mL of thoroughly degassed absoluteethanol was stirred at 50° C. for 30 minutes and then cooled slowly to0° C. The precipitate was collected and air dried to give 9.0 g ofN-(4-nitro-3-pyridinyl)-2-methyl-1H-indol-5-amine N⁵ -oxide as a powder.This powder was taken up in 135 mL of isopropanol and hydrogenated at50° C. over 3% platinum on carbon at 50 psi in the presence of lithiumhydroxide (0.26 g). Filtration and concentration left 8.0 g of a solidwhich was recrystallized from 32 mL of methanol giving 4.9 g ofcrystals. This material was then azeotroped repeatedly with absoluteethanol and dried at 85° C. to give 2.4 g of crystals, mp=96°-98° C.

Analysis: Calculated for C₁₆ H₂₀ N₄ O: 67.58% C, 7.09% H, 19.70% N;Found: 67.50% C, 7.05% H, 19.88% N.

EXAMPLE 24 N-(4-Amino-3-pyridinyl)-2-methyl-1H-indol-5-amine N⁵ -OxideHemihydrate

A mixture of 4-nitro-3-fluoropyridine N-oxide (5.4 g) and5-amino-2-methylindole (5.0 g) in 100 mL of thoroughly degassed absoluteethanol was stirred at 50° C. for 30 minutes and then cooled slowly to0° C. The precipitate was collected and air dried to give 8.2 g ofN-(4-nitro-3-pyridinyl)-2-methyl-1H-indol-5-amine N⁵ -oxide as a powder.This powder was taken up in 255 mL of absolute ethanol and hydrogenatedat room temperature over 3% platinum on carbon at 50 psi. Filtration andconcentration left 6.4 g of a solid which was purified by HPLC (7:3dichloromethane/methanol) to give 3.0 g of a powder which wasrecrystallized from methanol/ether to give 1.8 g of crystals, m.p.178-180 (with gas evolution).

Analysis: Calculated for C₁₄ H₁₄ N₄ O•0.5H₂ O: 63.86% C, 5.74% H, 21.24%N; Found: 63.70% C, 5.85% H, 20.84% N.

EXAMPLE 25 N-(4-Amino-3-pyridinyl)-2,3-dimethyl-1H-indol-5-amineEthanolate

A mixture of 4-nitro-3-fluoropyridine N-oxide (4.2 g) and5-amino-2,3-dimethylindole (4.2 g) in 100 mL of thoroughly degassedabsolute ethanol was stirred at 50° C. for 30 minutes and then cooledslowly to 0° C. The precipitate was collected and air dried to give 7.3g of N-(4-nitro-3-pyridinyl)-2,3-dimethyl-1H-indol-5-amine N⁵ -oxide asa powder. This powder was taken up in 225 mL of isopropanol andhydrogenated at 50° C. over 3% platinum on carbon at 50 psi in thepresence of lithium hydroxide (0.21 g). Filtration and concentrationleft 4.7 g of a solid which was recrystallized twice from methanolgiving 2.4 g of crystals. This material was then azeotroped repeatedlywith absolute ethanol and dried at 85° to give 1.4 g of crystals,mp=112°-115° C.

Analysis: Calculated for C₁₇ H₂₂ N₄ O: 68.43% C, 7.43% H, 18.78% N;Found: 68.31% C, 7.50% H, 18.61% N.

EXAMPLE 26N-(4-Amino-3-pyridinyl)-7-chloro-2,3-dimethyl-1H-indol-5-amine

A mixture of 4-nitro-3-fluoropyridine N-oxide (1.2 g) and5-amino-7-chloro-2,3-dimethylindole (1.4 g) in thoroughly degassedabsolute ethanol was stirred at 50° C. for 30 minutes and thereaftercooled slowly to 0° C. The precipitate was collected and air-dried togive 2.37 g ofN-(4-nitro-3-pyridinyl)-7-chloro-2,3-dimethyl-1H-indol-5-amine N⁵ -oxideas a powder.

This powder was added in portions to a slurry of titanium powder,prepared from 2.28 g of titanium tetrachloride and 0.45 g of lithiumaluminum hydride, in tetrahydrofuran at 0° C. The reaction mixture waswarmed to room temperature and stirred for four hours. The reactionmixture was quenched with dilute ammonium hydroxide and extracted intochloroform. Evaporation of the solvent left a solid which was purfied byflash chromatography to give 1.2 g of a powder, m.p. 108°-110° C.

We claim:
 1. A compound having the formula, ##STR13## where n is 0 or1;X is O or NR₂, R₂ being hydrogen, loweralkyl or loweralkylcarbonyl;and R₁ is ##STR14## or a pharmaceutically acceptable acid addition saltthereof.
 2. The compound as defined in claim 1, where X is O or NH. 3.The compound as defined in claim 1, where n is
 1. 4. The compound asdefined in claim 1, where X is O or NH, and n is
 1. 5. The compound asdefined in claim 1, which isN-(indan-5-yl)-4-nitro-3-pyridinamine-1-oxide.
 6. The compound asdefined in claim 1, which isN-(indan-1-yl)-4-nitro-3-pyridinamine-1-oxide.
 7. A dermatologicalcomposition which comprises a compound as defined in claim 1 in anamount effective for treating a skin disorder, and a suitable cardertherefor.
 8. A method of treating a patient in need of relief from askin disorder which comprises administering to such a patient aneffective amount of a compound as defined in claim 1.